Smoking is the main preventable cause of mortality in Western countries, contributing to over 430,000 deaths a year in the U.S. alone. Clinical and epidemiological studies show that women often decrease smoking in pregnancy, when endogenous progesterone levels are high. However, at least half resume pre-pregnancy smoking levels within weeks after delivery and when progesterone levels drop. Postpartum women who smoke increase their health risks and that of their offspring. No behavioral or medication treatments are clearly established as safe and effective for smoking cessation in postpartum women. Further, there is reluctance on the part of both postpartum women and obstetrical providers to use traditional anti-smoking medications since this may lead to neonatal exposure if the mother is breastfeeding. Given these concerns, there is a great need to develop relapse prevention treatments that are tailored for postpartum women with pre-conception smoking. Data from preclinical and clinical studies suggest that progesterone may be effective in preventing relapse to smoking in non-postpartum women, and may be acceptable to postpartum women and their providers. Prior work has shown that exogenous administration attenuates both craving for cigarettes and the subjective rewarding effects of smoking among recently abstinent female smokers. These findings led us to hypothesize that progesterone may have efficacy as a relapse prevention treatment for postpartum women. We propose an 8-week, randomized pilot study to evaluate the safety and initial efficacy of progesterone. This will be a feasibility study that will compare progesterone (200 mg/day) to placebo for relapse prevention in 40 postpartum smokers. We will assess the feasibility and safety, including the potential effects on breastfeeding and infants exposed via breast milk, in addition to 7-day point prevalence of smoking abstinence after 8 weeks of treatment and at follow-up, 3-months after the end of the protocol. If data suggest efficacy for progesterone, we will test the intervention i a larger clinical trial. Progesterone treatment, if ultimately found to be therapeutic, could be deployed in an obstetrical setting by providers that are accustomed to the use of progesterone as a therapeutic agent. Accordingly, the proposed project has the potential to make a major impact on the health of new mothers and their children.